Transdermal delivery system containing methylphenidate or its salts and methods thereof

ABSTRACT

Disclosed herein is a transdermal delivery system comprising methylphenidate or its salt as an active ingredient. Also provided are methods of delivering a therapeutically effective amount of methylphenidate to a subject for the treatment of a disease condition. The disease condition includes a neurological condition such as Attention Deficit Disorder (ADD) and/or Attention Deficit/Hyperactivity Disorder (ADHD). Kits including the transdermal delivery system and methods of making and using the transdermal delivery system are also provided.

RELATED APPLICATION

This application is a continuation application of U.S. patent Ser. No.15/634,188, filed on Jun. 27, 2017, which claims the benefit of U.S.provisional application Ser. No. 62/357,316, filed Jun. 30, 2016, whichare hereby incorporated by reference in their entirety.

INTRODUCTION

Disclosed herein is a transdermal delivery system comprisingmethylphenidate or its pharmaceutically acceptable salt as an activeingredient. Also provided are methods of delivering a therapeuticallyeffective amount of methylphenidate to a subject for the treatment of adisease condition. The disease condition includes a neurologicalcondition such as Attention Deficit Disorder (ADD) and/or AttentionDeficit/Hyperactivity Disorder (ADHD). Kits including the transdermaldelivery system and methods of making and using such delivery system arealso provided.

BACKGROUND

It has been reported that ADD and/or ADHD are developmental disordersthat consists of attention span, impulse control and self-control. Ithas been reported that though the pathogenesis of ADD and/or ADHD hasnot been fully investigated, it is known that traditionally,methylphenidate has been used in the treatment of ADD and/or ADHD forboth children and adults. It is also known that methylphenidate can alsobe used in the treatment of diseases including but not limited topostural orthostatic tachycardia syndrome and narcolepsy.

Daytrana® (methylphenidate transdermal system) is available in fourdosage strengths (10, 15, 20 and 30 mg/day) and is applied for 9 hoursusing patch sizes correlated with the dose (12.5, 18.75, 25 and 37.5cm2, respectively). Daytrana® is a polymer matrix comprising an acrylicpressure-sensitive adhesive. However, the peel force from the releaseliner of the patch increases over time. This creates a serious issue aspatients may encounter difficulties or unable to remove the releaseliner for use. In addition, it has been reported that currentlyavailable methylphenidate patches have leaking issues where themethylphenidate leaks out of the patch. This also creates a problemwhere the large size patches are too soft to handle. This problem ismore severe if the methylphenidate patches are stored for several monthsor longer. See US20140271792 A1, US 2016/0030362 A1 and NDA 21-514 CMCreview. In addition, currently available methylphenidate patches havelow permeation and flux rate (˜9.1 μg/cm2 hr see US 2016/0030362 A1). Asmethylphenidate will cause skin sensitization (Daytrana® package insert,Cheng C. J of Pediatrics January 2017 Vol 180, P 241-246), whencompensate for the low permeation rate, larger patches are needed, i.e.37.5 cm².

Therefore, there is a need to develop an optimal methylphenidateformulation with high flux to reduce drug loading and patch size tominimize the skin sensitization and exhibit suitable physical andpharmacokinetic properties. The presently disclosed transdermal deliverysystem has a higher permeation and flux rate than previously knownmethylphenidate transdermal delivery system in the market. Because ofthese improved properties, the same or more of the active pharmaceuticalagents can be delivered. The patches of the present disclosure do nothave the currently undesirable issues for being leaky, too soft tohandle and too large to be comfortably applied to a patient. Thepresently disclosed methylphenidate transdermal delivery system improvesthe quality of life of caregivers and patients who are suffering fromADD and/or ADHD, postural orthostatic tachycardia syndrome andnarcolepsy (Findling R, Dinh S, CNS Drugs (2014) 28:217-228).

3. SUMMARY

It is discovered that a transdermal delivery system comprising: (i) asilicone layer; (ii) a drug-containing matrix layer that comprises: (a)methylphenidate or its pharmaceutically acceptable salt; and (b) arubber based polymer comprising a tackifier, has improved permeation andflux over the current methylphenidate transdermal delivery system in themarket by about 60%-70%. This dramatic increase in permeation and fluxof the presently disclosed methylphenidate transdermal delivery systemprovide superior improvements to the lives of the patients.

An object of the present disclosure is to provide a method and a systemfor transdermal delivery of methylphenidate or its salt as an activeingredient to a subject through skin or other body surface.

The transdermal delivery system comprises a backing layer, a siliconelayer, a drug-containing matrix layer, and a release liner. The systemcan be applied to the skin or the mucosa of a subject over an extendedperiod of time without side effects.

In one embodiment, the transdermal delivery system comprises: (a) asilicon adhesive layer; and (b) a rubber-based polymer that comprises ahydrogenated synthetic hydrocarbon tackifier has the followingproperties: (i) exhibits good adherence to skin; (ii) ability to bepeeled or removed without substantial trauma to the skin; (iii)retention of tackiness over time. In one embodiment, the release linercan be removed from the presently disclosed transdermal delivery systemwithout losing the drug-containing matrix to the release liner. In oneembodiment, the transdermal delivery system does not suffer from peelrelease problems associated with other methylphenidate transdermaldelivery system. In one embodiment, the transdermal delivery system hasa lower residual drug content after application than a transdermaldelivery system that does not comprise a silicone adhesive layer. Thepresence of a silicon adhesive layer between the backing layer and thedrug-containing matrix layer improves permeation of the drugs from thetransdermal system to the subject.

Also disclosed is a transdermal system having improved drug loading withdesirable tack and adhesion. In one embodiment, the transdermal systemcomprises an adhesive. In one embodiment, the transdermal systemcomprises more than one type of copolymer in the drug-containing matrixlayer.

In one embodiment, the methylphenidate transdermal delivery system ofthe present disclosure comprises methylphenidate as the activepharmaceutical ingredient which may be in free base form or apharmaceutically acceptable salt thereof. In one embodiment, themethylphenidate transdermal delivery system further comprises arubber-based polymer comprising a tackifier for providing adhesiveproperty. In one embodiment, the rubber-based polymer comprisesstyrene-butadiene block copolymer rubber. In one embodiment, thestyrene-butadiene block copolymer rubber comprises a hydrogenatedsynthetic hydrocarbon tackifier. In one embodiment, the methylphenidatetransdermal delivery system further comprises one or more excipients. Inone embodiment, the silicone adhesive layer provides an increased flux.In one embodiment, the transdermal delivery system increased flux ofmethylphenidate from the transdermal delivery system to the user's skinby lowering solubility of the methylphenidate or its pharmaceuticallyacceptable salt in the transdermal delivery system relative to thesolubility of the methylphenidate or its pharmaceutically acceptablesalt in the stratum corneum layer of the user's skin.

Importantly, while capable of improving the flux, the one or moreexcipients would preferably not affect the stability of the transdermaldelivery system. Specifically, since methylphenidate is reactive withsubstances such as bases, water and oxidants, the one or more excipientsshould not be, nor contain substances that degrade methylphenidate.Therefore, the one or more excipients preferably are not, does notcontain nor does not attract base, water, oxidant and/or any substancesthat may degrade methylphenidate, but are found to substantiallyincrease flux. In an embodiment, the one or more excipients comprise oneor more saturated carbohydrates. More specifically, in certainembodiments, the one or more excipients comprise squalane, isosqualane,monocyclosqualane, hemisqualane, sesquisqualane, squalene and/orcyclomethicone.

In certain embodiments, more than one excipients are combined in orderto optimize the flux while not detrimentally affecting the stability ofthe transdermal delivery system.

In an embodiment, the methylphenidate transdermal delivery systemcomprises methylphenidate free base, styrene-butadiene block copolymerrubber wherein the methylphenidate free base comprises about 5% to about20% by total weight, styrene-butadiene block copolymer rubber comprisesabout 70% to about 90% by total weight.

In order to lend adhesive property to the composition, in oneembodiment, the methylphenidate transdermal delivery system furthercomprises a tackifier. In one embodiment, the drug-containing matrixdoes not contain any added tackifier. In addition, in order to increasestability of the transdermal delivery system, in one embodiment, thetransdermal delivery system further comprises an antioxidant. In oneembodiment, the methyophenidate transdermal delivery system furthercomprises one or more permeation enhancers in addition to the one ormore excipients.

In certain embodiments, the drug transdermal delivery system comprises amatrix which comprises methylphenidate or its salt dispersed therein. Incertain embodiments, the system and method include a matrix formed of apolymer and methylphenidate or its salt dispersed uniformly within thepolymer.

In one embodiment, provided herein is a transdermal delivery systemwhich comprises: (i) a backing layer; (ii) a silicone adhesive layer;(iii) a drug-containing matrix layer comprising methylphenidate or itspharmaceutically acceptable salt, styrene-butadiene block copolymerrubber and hydrogenated synthetic hydrocarbon tackifier; and (iv) arelease liner.

In certain embodiments, the methylphenidate or its pharmaceuticallyacceptable salt is about 5 to about 30% by weight based on the totalweight of the drug-containing matrix layer. In certain embodiments, themethylphenidate or its pharmaceutically acceptable salt is about 8,about 12, about 14 or about 20% by weight based on the total weight ofthe drug-containing matrix layer. In certain embodiments, the firstlayer comprises about 75-78%, 78-80%, 80-90%, 90-100% by weight ofsilicone. In certain embodiments, the styrene-butadiene block copolymerrubber and hydrogenated synthetic hydrocarbon tackifier is about 70-80%,80-95% by weight based on the total weight of the drug containing matrixlayer.

In certain embodiments, the silicone adhesive layer has a thickness fromabout 20 μm to about 60 μm.

In certain embodiments, the drug-containing matrix layer has a thicknessfrom about 20 μm to about 60 μm. In certain embodiments, the system hasa flux of about 10-44 μg/cm² hr. In certain embodiments, themethylphenidate or its pharmaceutically acceptable salt is about 8-20%by weight of the drug-containing matrix layer.

In one embodiment, the present disclosed transdermal delivery systemachieves high flux in a system with a smaller active surface area ascompared to other methylphenidate transdermal delivery system. In oneembodiment, the transdermal delivery system has a unit size having adimension of less than 40 cm². The disclosed transdermal delivery systemoffers high advantages of cost savings and improved patient compliance.

In one embodiment, the transdermal delivery system releases at leastabout 80% methylphenidate within 12 hours in an in vitro dissolutionmedia at about pH1.2.

While the actual flux may vary, in certain embodiments, the skinpermeation rates are about 3-4 μg/cm²/hr, about 4-5 μg/cm²/hr, about 5-6μg/cm²/hr, about 6-7 μg/cm²/hr, about 7-8 μg/cm²/hr, about 8-9μg/cm²/hr, about 9-10 μg/cm²/hr, about 10-11 μg/cm²/hr, or about 11-12μg/cm²/hr, about 12-15 μg/cm²/hr, about 15-20 μg/cm²/hr, about 20-25μg/cm²/hr, about 25-30 μg/cm²/hr, about 30-35 μg/cm²/hr, about 35-40μg/cm²/hr, about 40-45 μg/cm²/hr, or about 45-50 μg/cm²/hr.

In certain embodiments, the flux is about 13-44 μg/cm² hr.

In certain embodiments, the transdermal delivery systems are formulatedto provide a cumulative delivered amount (also referred to herein ascumulative flux) of the active agent to a subject when the formulationis applied to the skin of a subject for an extended period of time asdescribed infra. In certain embodiments, the transdermal formulationsare configured to provide a cumulative delivered amount of the activeagent of about 1-100 μg/cm², about 100-150 μg/cm², about 150-200 μg/cm²,about 200-250 μg/cm², about 250-300 μg/cm², about 300-350 μg/cm², about350-400 μg/cm², about 400-450 μg/cm², about 450-500 μg/cm², about500-550 μg/cm², about 550-600 μg/cm², about 600-650 μg/cm², 650-700μg/cm², about 700-750 μg/cm², 750 m-800 μg/cm², 800-850 μg/cm2, about850-900 μg/cm², about 900-950 μg/cm², or about 950-1000 μg/cm².

The size (i.e., area) of the transdermal delivery system may vary, butis within a range of the active agent to the subject. It is alsoimportant that the subject wearing the transdermal delivery system findsthe system to be easy to apply and comfortable to use for a period oftime so as to improve compliance. In certain embodiments, the size ofthe formulation is chosen in view of the desired transdermal flux rateof the active agent and the target dosage. In certain embodiments, thetransdermal delivery system has a size that is about 2-6 cm², about 6-10cm², about 10-20 cm², about 20-30 cm², about 30-40 cm², about 40-50 cm²,about 50-100 cm², about 100-130 cm², about 130-140 cm², about 140-150cm² or about 150-200 cm².

The transdermal delivery system of the present disclosure is formulatedto provide a therapeutically effective amount of the active agent to asubject when the topical patch is applied to a skin site of a subjectfor an extended period of time (e.g., a multi-day period of time). Forexample, the extended period of time may be a period of time that isabout 6-12 hours, about 12-24 hours, about 1-2 days.

In certain embodiments, the AUC0-t, is about 80-120 h·ng/mL, 120-160h·ng/mL, 160-200 h·ng/mL, 200-240 h·ng/mL, 240-280 h·ng/mL, 280-320h·ng/mL, 320-360 h·ng/mL, 360-400 h·ng/mL 400-440 h·ng/mL 440-480h·ng/mL. In certain embodiments, the AUC_(0-∞) is about 80-120 h·ng/mL,120-160 h·ng/mL, 160-200 h·ng/mL, 200-240 h·ng/mL, 240-280 h·ng/mL,280-320 h·ng/mL, 320-360 h·ng/mL, 360-400 h·ng/mL 400-440 h·ng/mL440-480 h·ng/mL. In certain embodiments, the C_(max) is about 8-12ng/mL, 12-16 ng/mL, 16-20 ng/mL, 20-24 ng/mL, 24-28 ng/mL, 28-32 ng/mL,32-36 ng/mL, 36-40 ng/mL, 40-44 ng/mL. In certain embodiments, theT_(max), is 4-6 hrs, 6-8 hrs, 8-10 hrs, 10-12 hrs, 12-14 hrs.

In one embodiment, provided herein is a transdermal delivery systemwhich comprises: (i) a backing layer; (ii) a silicone layer; (iii) adrug-containing matrix layer comprising methylphenidate free base,styrene-butadiene block copolymer rubber comprising a hydrogenatedsynthetic hydrocarbon tackifier; and (iv) a release liner.

Also provided herein is a method of making the transdermal deliverysystem.

In one embodiment, the method of making the transdermal delivery systemcomprises the following steps: First, a desired amount ofmethylphenidate is dissolved into styrene-butadiene copolymer comprisinga hydrogenated synthetic hydrocarbon tackifier with solvent to form adrug-containing mixture. Examples of solvents that may be used aretoluene, hexane, heptane, ethyl acetate or other solvents appropriatefor dissolving methylphenidate or a pharmaceutically acceptable saltthereof. Then, optionally, enhancers and other excipients are added intothe mixture. After gentle mixing for 20 minutes or until every componentis uniformly dispersed, a matrix is created. Next, the mixture allowedit to stand to deaerate. Vacuum and centrifugation may be employed toshorten the deaeration time. A silicone adhesive layer is laminated ontoone side of a supportive backing layer. After deaeration of the mixture,laminate the matrixed mixture uniformly onto silicone adhesive layer ofthe supportive backing layer with controlled thickness in order toachieve a wet film. Next, dry the wet film in high temperature and/orunder strong fan to eliminate the solvent. The dried film will then belaminated with a releasing liner to protect the adhesive side of dryfilm which is then cropped into desired dimension and formed the patchproduct.

Further provided herein is a method for controlled and sustaineddelivery of therapeutic amounts of methylphenidate or itspharmaceutically acceptable salt to a subject.

In some embodiments, the method includes a controlled and sustained drugdelivery system useful to deliver Methylphenidate and its salt to apatient. The system comprises delivery of substantially homogeneousparticles. In certain embodiments, the substantially homogeneousparticles are dispersed in a rubber-based polymer matrix. Also disclosedis the method of preparing a drug-containing matrix.

When compared with other methylphenidate transdermal delivery system,the present transdermal delivery system provides 1.2-3, 3-4, 4-5, 5-6,6-7, 7-8, 8-9, 9-10, 10-11, or 11-12 folds higher flux rate. Inparticular, the present methylphenidate transdermal delivery systemprovides 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, or 8-9 folds higher flux rate ascompared with a control methylphenidate transdermal delivery system thatdoes not comprise a silicone adhesive layer.

In certain embodiments, the transdermal delivery system provideseffective administration of methylphenidate at a flux rate ranging fromabout 6 μg/cm²/hr-100 μg/cm²/hr. In certain embodiments, the transdermaldelivery system provides effective administration of methylphenidate ata flux rate ranging from about 6 μg/cm²/hr-10 μg/cm²/hr, 10 μg/cm²/hr-15μg/cm²/hr, 15 μg/cm²/hr-20 μg/cm²/hr, 20 μg/cm²/hr-25 μg/cm²/hr, 25μg/cm²/hr-30 μg/cm²/hr, 30 μg/cm²/hr-35 μg/cm²/hr, 35 μg/cm²/hr-40μg/cm²/hr, 40 μg/cm²/hr-45 μg/cm²/hr, 45 μg/cm²/hr-50 μg/cm²/hr, 50μg/cm²/hr-55 μg/cm²/hr, 55 μg/cm²/hr-60 μg/cm²/hr, 60 μg/cm²/hr-65μg/cm²/hr, 65 μg/cm²/hr-70 μg/cm²/hr, 70 μg/cm²/hr-75 μg/cm²/hr, 75μg/cm²/hr-80 μg/cm²/hr, 80 μg/cm²/hr-85 μg/cm²/hr, 85 μg/cm²/hr-90μg/cm²/hr, 90 μg/cm²/hr-95 μg/cm²/hr, or 95 μg/cm²/hr μg/cm²/hr-100μg/cm²/hr.

In certain embodiments, the transdermal delivery system provideseffective administration of methylphenidate at a flux rate ranging fromabout 6 μg/cm²/hr-10 μg/cm²/hr, 10 μg/cm²/hr-15 μg/cm²/hr, 15μg/cm²/hr-20 μg/cm²/hr, 20 μg/cm²/hr-25 μg/cm²/hr, 25 μg/cm²/hr-30μg/cm²/hr, 30 μg/cm²/hr-35 μg/cm²/hr, 35 μg/cm²/hr-40 μg/cm²/hr, 40μg/cm²/hr-45 μg/cm²/hr, 45 μg/cm²/hr-50 μg/cm²/hr, 50 μg/cm²/hr-55μg/cm²/hr, 55 μg/cm²/hr-60 μg/cm²/hr, 60 μg/cm²/hr-65 μg/cm²/hr, 65μg/cm²/hr-70 μg/cm²/hr, 70 μg/cm²/hr-75 μg/cm²/hr, 75 μg/cm²/hr-80μg/cm²/hr, 80 μg/cm²/hr-85 μg/cm²/hr, 85 μg/cm²/hr-90 μg/cm²/hr, 90μg/cm²/hr-95 μg/cm²/hr, or 95 μg/cm²/hr μg/cm²/hr-100 μg/cm²/hr, for atleast 2-4 hours, 4-6 hours, 6-8 hours, 8-10 hours, 10-12 hours, 12-14hours, 14-16 hours, 16-18 hours, 18-20 hours, 20-22 hours, or 22-24hours after treatment is initiated.

In certain embodiments, the transdermal delivery system provides atherapeutically effective flux rate of methylphenidate ranging fromabout 6 μg/cm²/hr-10 μg/cm²/hr, 10 μg/cm²/hr-15 μg/cm²/hr, 15μg/cm²/hr-20 μg/cm²/hr, 20 μg/cm²/hr-25 μg/cm²/hr, 25 μg/cm²/hr-30μg/cm²/hr, 30 μg/cm²/hr-35 μg/cm²/hr, 35 μg/cm²/hr-40 μg/cm²/hr, 40μg/cm²/hr-45 μg/cm²/hr, 45 μg/cm²/hr-50 μg/cm²/hr, 50 μg/cm²/hr-55μg/cm²/hr, 55 μg/cm²/hr-60 μg/cm²/hr, 60 μg/cm²/hr-65 μg/cm²/hr, 65μg/cm²/hr-70 μg/cm²/hr, 70 μg/cm²/hr-75 μg/cm²/hr, 75 μg/cm²/hr-80μg/cm²/hr, 80 μg/cm²/hr-85 μg/cm²/hr, 85 μg/cm²/hr-90 μg/cm²/hr, 90μg/cm²/hr-95 μg/cm²/hr, or 95 μg/cm²/hr μg/cm²/hr-100 μg/cm²/hr, for atleast 2-4 hours, 4-6 hours, 6-8 hours, 8-10 hours, 10-12 hours, 12-14hours, 14-16 hours, 16-18 hours, 18-20 hours, 20-22 hours, or 22-24hours after treatment is initiated.

In certain embodiments, the drug-containing matrix layer contains fromabout 2% to about 20% w/w methylphenidate and provides a therapeuticallyeffective flux rate ranging from about 6 μg/cm²/hr-10 μg/cm²/hr, 10μg/cm²/hr-15 μg/cm²/hr, 15 μg/cm²/hr-20 μg/cm²/hr, 20 μg/cm²/hr-25μg/cm²/hr, 25 μg/cm²/hr-30 μg/cm²/hr, 30 μg/cm²/hr-35 μg/cm²/hr, 35μg/cm²/hr-40 μg/cm²/hr, 40 μg/cm²/hr-45 μg/cm²/hr, 45 μg/cm²/hr-50μg/cm²/hr, 50 μg/cm²/hr-55 μg/cm²/hr, 55 μg/cm²/hr-60 μg/cm²/hr, 60μg/cm²/hr-65 μg/cm²/hr, 65 μg/cm²/hr-70 μg/cm²/hr, 70 μg/cm²/hr-75μg/cm²/hr, 75 μg/cm²/hr-80 μg/cm²/hr, 80 μg/cm²/hr-85 μg/cm²/hr, 85μg/cm²/hr-90 μg/cm²/hr, 90 μg/cm²/hr-95 μg/cm²/hr, or 95 μg/cm²/hrμg/cm²/hr-100 μg/cm²/hr, for at least 2-4 hours, 4-6 hours, 6-8 hours,8-10 hours, 10-12 hours, 12-14 hours, 14-16 hours, 16-18 hours, 18-20hours, 20-22 hours, or 22-24 hours after treatment is initiated.

In certain embodiments, the drug-containing matrix layer releases40%-50%, 50%-60%, 60%-70% or 70%-80% of methylphenidate within 10-12hours after treatment is initiated.

In certain embodiments, the drug-containing matrix layer is color-stableand lacks crystal growth of the active ingredient, over an extendedstorage period of at least 2 years at room temperature.

In one embodiment, the transdermal delivery system comprises: (i) asilicone adhesive layer; and (ii) a drug-containing matrix layercomprising: (a) methylphenidate or its pharmaceutically acceptable salt;and (b) a rubber-based polymer that comprises a hydrogenated synthetichydrocarbon tackifier, wherein the transdermal delivery system has aflux rate ranging from about 6 μg/cm²/hr-100 μg/cm²/hr between 2-18hours after treatment is initiated.

Provided herein is a method for delivering drugs to a patient comprisingthe step of administering the transdermal delivery system disclosedherein.

Provided herein is a method for administering methylphenidate to a humansubject in need thereof, which method comprises: (1) providing atransdermal delivery system comprising: (i) a silicon layer; (ii) adrug-containing matrix layer that comprises at least about 2% to about20% w/w methylphenidate or its pharmaceutically acceptable salt thereofwhich provides a therapeutically effective flux rate ranging from about6 μg/cm²/hr-10 μg/cm²/hr, 10 μg/cm²/hr-15 μg/cm²/hr, 15 μg/cm²/hr-20μg/cm²/hr, 20 μg/cm²/hr-25 μg/cm²/hr, 25 μg/cm²/hr-30 μg/cm²/hr, 30μg/cm²/hr-35 μg/cm²/hr, 35 μg/cm²/hr-40 μg/cm²/hr, 40 μg/cm²/hr-45μg/cm²/hr, 45 μg/cm²/hr-50 μg/cm²/hr, 50 μg/cm²/hr-55 μg/cm²/hr, 55μg/cm²/hr-60 μg/cm²/hr, 60 μg/cm²/hr-65 μg/cm²/hr, 65 μg/cm²/hr-70μg/cm²/hr, 70 μg/cm²/hr-75 μg/cm²/hr, 75 μg/cm²/hr-80 μg/cm²/hr, 80μg/cm²/hr-85 μg/cm²/hr, 85 μg/cm²/hr-90 μg/cm²/hr, 90 μg/cm²/hr-95μg/cm²/hr, or 95 μg/cm²/hr μg/cm²/hr-100 μg/cm²/hr, for at least 2-4hours, 4-6 hours, 6-8 hours, 8-10 hours, 10-12 hours, 12-14 hours, 14-16hours, 16-18 hours, 18-20 hours, 20-22 hours, or 22-24 hours aftertreatment is initiated; and (2) applying the transdermal delivery systemto an area of skin of the subject in an amount sufficient to provide atherapeutic concentration of methylphenidate in the bloodstream of thesubject.

In certain embodiments, the method comprises applying up to about 4mg-60 mg of methylphenidate to a skin surface area of about 2 cm²-60cm².

In certain embodiments, the method comprises applying the transdermaldelivery system on the abdomen, thigh, behind an ear, or on a shoulderor upper arm of a subject.

In certain embodiment, the method comprises applying the transdermaldelivery system in a daily single dose.

In certain embodiments, the transdermal therapeutic system applied inthe method provides a rate of administration of methylphenidate rangingfrom about 6-100 μg per hour over 16 hours after treatment is initiated.

In certain embodiments, the transdermal therapeutic system providessustained, steady-state delivery of about 6-100 μg per hour over 10hours after treatment is initiated.

In certain embodiments, the transdermal therapeutic system providessustained, steady-state delivery of about 6-100 μg per hour over 16hours after treatment is initiated.

In certain embodiments, the transdermal therapeutic system providessustained, steady-state delivery of about 6-100 μg per hour over 18hours after treatment is initiated.

In certain embodiments, the transdermal therapeutic system providessustained, steady-state delivery of about 6-100 μg per hour over 24hours after treatment is initiated.

Also described herein is a transdermal delivery system used to treat orprevent diseases in a subject. In a specific embodiment, the subject isa mammal. In a specific embodiment, the subject is human. In oneembodiment, provided herein is a method of treating a disease comprisingadministering to a subject, a transdermal delivery system comprising atherapeutically effective amount of methylphenidate or its salt.

Also disclosed is a kit comprising the transdermal delivery systemprovided herein. The kit comprises a carrier being compartmentalized toreceive in close confinement one or more containers comprising one ofthe separate elements to be used in the method. The kit also containsinstructions for administering the transdermal delivery system.

A kit as provided herein comprises a unit dose of methylphenidate or itssalt provided herein, such that when administered to a subject, atherapeutically or prophylactically effective plasma level of thecompound or composition can be maintained in the subject for at least1-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-22,22-24 hours. In certain embodiments, the therapeutically orprophylactically effective plasma level of the compound or compositioncan be maintained in the subject for at least 1, 2, 3, 4, 5, and 7 day.

These and other aspects, features, and advantages can be appreciatedfrom the accompanying description of certain embodiments of thedisclosure and the accompanying drawing figures and claims.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows is a schematic diagram comparing permeation mechanism ofactive ingredient from a transdermal delivery system that does notcomprise a silicone layer versus a transdermal delivery system thatcomprises a silicon layer.

FIG. 2 shows the average permeation rate comparison between twotransdermal delivery system. Bottom curve: Transdermal delivery systemcomprising 17% Methylphenidate without a silicon layer. Top curve:Transdermal delivery system comprising a silicon adhesive layer and adrug-containing layer comprising 17% Methylphenidate. The graph measuresflux rate (μg/ml/cm²/hr) vs. time (Hr).

FIG. 3 shows the average cumulative amount comparison between twotransdermal delivery system. Bottom curve: Transdermal delivery systemcomprising 17% Methylphenidate without a silicon adhesive layer. Topcurve: Transdermal delivery system comprising a silicon adhesive layerand a drug-containing layer comprising 17% Methylphenidate. The graphmeasures cumulative amount permeated (μg/cm²) vs. time (Hr).

FIG. 4 shows a graph of shearing adhesion vs. different % drug loading.Generally, higher drug content lowers the shearing force.

FIG. 5 shows healthy subject pharmacokinetics profile

FIG. 6 shows in vitro dissolution profile of Example 8.

FIG. 7 shows in vitro permeation profile of accumulated amount fromdifferent acrylate adhesives.

FIG. 8 shows linear relationship between drug loading and in vitropermeation rate for the bilayer formulations.

DEFINITIONS

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “subjects” refer to an animal,such as a mammal including a non-primate (e.g., a cow, pig, horse, cat,dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgousmonkey, a chimpanzee and a human). In one embodiment, the subject is ahuman.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating a disease or disorder that exists in asubject. In another embodiment, “treating” or “treatment” includesameliorating at least one physical parameter, which may be indiscernibleby the subject. In yet another embodiment, “treating” or “treatment”includes modulating the disease or disorder, either physically (e.g.,stabilization of a discernible symptom) or physiologically (e.g.,stabilization of a physical parameter) or both. In yet anotherembodiment, “treating” or “treatment” includes delaying the onset of thedisease or disorder.

As used herein, the terms “preventing” and “prevention” of any diseaseand disorder refers to the prevention of a disorder or one or moresymptoms thereof. Preventing and prevention is to impede the onset,development, and progression of disorder or symptoms.

As used herein, the term “about” is defined as a deviation of ±5% from anumerical value.

The term “Methylyphenidate or its pharmaceutically acceptable salt”means methylphenidate free base or a methylphenidate salt that induces adesired pharmacological or physiological effect, and includes agentsthat are therapeutically effective or prophylactically effective. Theterms also encompass pharmacologically active derivatives and analogs ofthose active agents specifically mentioned herein, including, but notlimited to, salts, esters, amides, sulfates, prodrugs, activemetabolites, inclusion complexes and the like.

The term “effective amount” or “a therapeutically effective amount” of adrug or pharmacologically active agent is intended to mean a nontoxicbut sufficient amount of the drug or active agent for providing thedesired therapeutic effect. The amount that is “effective” will varyfrom subject to subject, depending on the age and general condition ofthe individual, the particular active agent or agents, and the like. Anappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

As used herein, the term “styrene-butadiene block copolymer” is definedas copolymer of monomers containing styrene and butadiene.

As used herein, the terms “topical” and topically” mean application to askin or mucosal surface of a mammal, while the terms “transdermal” meanspassage through the skin or mucosa (including oral, buccal, nasal,rectal and vaginal mucosa), into systemic circulation. Thus, thecompositions described herein may be applied topically to a subject toachieve transdermal delivery of methylphenidate.

As used herein, the term “drug-containing matrix” means a compositioncomprising one or more drugs, such as methylphenidate, and arubber-based polymer optionally comprising a hydrogenated synthetichydrocarbon tackifier.

DETAILED DESCRIPTION

In the following detailed description, numerous specific details are setforth to provide a thorough understanding of claimed subject matter.However, it will be understood by those skilled in the art that claimedsubject matter may be practiced without these specific details. In otherinstances, methods, apparatuses, or systems that would be known by oneof ordinary skill have not been described in detail so as not to obscureclaimed subject matter. It is to be understood that particular features,structures, or characteristics described may be combined in various waysin one or more implementations.

Multi-Layer Structure of the Transdermal Delivery System

Disclosed herein is a flexible, finite system that is a solid formcapable of conforming to the surface with which it comes into contact.The system is capable of maintaining the contact in such solid form soas to facilitate topical application without adverse physiologicalresponse, and without being decomposed by contact on dry or wet surfacesduring administration to a subject. Flexible, finite systems that areknown in the art include, films, plasters, dressings, and bandages, aswell as multi-layer delivery systems in which the drug is solubilized orcontained in a reservoir or depot separate from the matrix whichattaches directly to the skin or mucosa. In one embodiment, the drug isin a matrix.

In one embodiment, the transdermal delivery system described hereincomprises a backing layer, a silicone adhesive layer, a drug-containingmatrix layer comprising: (i) methylphenidate and its pharmaceuticallyacceptable salt; (ii) rubber-based polymer that comprises a hydrogenatedsynthetic hydrocarbon tackifier, and a release liner. In one embodiment,the rubber-based polymer is styrene-butadiene block copolymer. In oneembodiment, the rubber-based polymer is not styrene-isoprene-styrenepolymer. In one embodiment, the rubber-based polymer is notpolyisobutylene.

Methylphenidate (a-phenyl-2-piperidineacetic acid methyl ester) is achiral drug. While commercially available methylphenidate products (suchas the oral product Ritalin® tablets and the transdermal productDaytrana®) patch include a 50:50 (racemic) mixture of d- andl-threo-methylphenidate, it is believed that the d-threo-methylphenidateisomer has greater pharmacological activity. The compositions describedherein may be formulated with any isomer of methylphenidate, althoughcompositions comprising a racemic mixture of d- andl-threo-methylphenidate, or comprising primarily thed-threo-methylphenidate isomer may be most commercially relevant.

The compositions described herein may be formulated with methylphenidatefree base (“methylphenidate base”), any pharmaceutically acceptable saltthereof, or mixtures thereof. Exemplary suitable pharmaceuticallyacceptable salts of methylphenidate are salts of weak inorganic andorganic acids, and quaternary ammonium salts. These include withoutlimitation, salts with acids such as sulfuric, phosphoric, hydrochloric,hydrobromic, hydriodic, sulfamic, citric, lactic, maleic, malic,succinic, tartaric, cinnamic, acetic, benzoic, gluconic, or ascorbicacid, or quaternary ammonium salts with organic esters of sulfuric,hydrohalic, or aromatic sulfonic acids, such as methyl chloride, methylbromide, ethyl chloride, propyl chloride, butyl chloride, isobutylchloride, benzylchloride, benzyl bromide, phenethyl bromide,naphthymethyl chloride, dimethyl sulfate, methyl benzenesulfonate, ethyltoluenesulfonate, ethylene chlorohydrin, propylene chlorobydrin, allylbromide, methylallyl bromide or crotyl bromide esters.

Methylphenidate, including methylphenidate base in particular, has asecondary amine moiety and a methyl ester moiety, and is unstable andundergoes degradation in the presence of reactive functional groups,such as active hydrogen atoms or functional groups with hydrogen atomsavailable for chemical reaction or interaction with methylphenidate,such as, for example, carboxyl, hydroxyl, amine, thiol, silanol or epoxygroups, which may be present in polymers, enhancers, excipients andother components that typically may be used in transdermal compositions.Major degradants of methylphenidate include ritalinic acid and erytholisomer, whose concentrations increase significantly with increasingamounts (by weight) of functional groups. Such degradation can greatlyreduce the amount of the active species present in a composition afterstorage, thus reducing the amount of active methylphenidate availablefor drug delivery. Thus, in some embodiments, the compositions describedherein are formulated without components that have such functionalgroups. That is, in some embodiments, the compositions described hereinare formulated only with non-reactive components as defined above anddiscussed in more detail below.

The compositions described herein include a therapeutically effectiveamount of methylphenidate or pharmaceutically acceptable salt thereof.Generally, the amount of methylphenidate is from about 5% to about 20%,including from about 5% to about 15%, such as from about 10% to about19% by weight, or from about 15% to about 18% by weight, based on thetotal dry weight of the drug-containing matrix. In specific embodiments,the drug-containing matrix comprises about 17% by weightmethylphenidate, based on the total dry weight of the drug-containingmatrix.

In accordance with any of the embodiments described herein, thecomposition may include from about 20 to about 225 mg per unit ofmethylphenidate base or an equivalent amount of a pharmaceuticallyacceptable salt thereof.

The amount of methylphenidate and its pharmaceutically acceptable saltpresent in the drug-containing matrix layer may vary. In certainembodiments, the amount of methylphenidate and its pharmaceuticallyacceptable salt deliver methylphenidate ranges from about 4 mg to about60 mg. In certain embodiments, the methylphenidate and itspharmaceutically acceptable salt ranges from about 4-8 mg, about 8-10mg, about 10-12 mg, about 12-14 mg, about 14-16 mg, about 16-18 mg,about 18-20 mg, about 20-24 mg, about 24-28 mg, about 28-30 mg, about30-35 mg, about 35-40 mg, about 40-45 mg, about 45-50 mg, about 50-55mg, or about 55-60 mg per unit of the transdermal delivery system. Inone embodiment, a unit of the transdermal delivery system is one dose ofthe transdermal delivery system. In one embodiment, one dose is onepatch. In certain embodiments, the methylphenidate and itspharmaceutically acceptable salt present in the drug-containing matrixlayer is about 0.01-0.05%, about 0.05%-0.1%, about 0.1-0.2%, about0.2-0.5%, about 0.5-1%, about 1-2%, about 2-4%, about 2-5%, about 5-6%,about 6-7%, about 7-8%, about 8-9%, about 9-10%, about 10-13%, about13-14%, about 14-15%, about 15-16%, about 16-17%, about 17-18%, about18-19%, about 19-20%, or about 20-25%, by weight based on the totalweight of the drug-containing matrix layer. In certain embodiments, themethylphenidate and its pharmaceutically acceptable salt is about0.01-5% by weight based on the total weight of the drug-containingmatrix layer. In certain embodiments, the methylphenidate and itspharmaceutically acceptable salt is about 1-16% by weight based on thetotal weight of the drug-containing matrix layer. In certainembodiments, the methylphenidate and its pharmaceutically acceptablesalt is about 0.5-1, 1-2.5, 2.5-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10,10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 17-18, 18-19, 19-20% byweight based on the total weight of the drug-containing matrix layer.

The drug-containing matrix layer comprises methylphenidate or itspharmaceutically acceptable salt. In one embodiment, the methylphenidateis methylphenidate free base. In certain embodiments, thedrug-containing matrix layer includes one or more active agents, whichagents are methylphenidate and its pharmaceutically acceptable salt.

Silicone Adhesive Layer

It is discovered that a silicone adhesive layer in the methylphenidatetransdermal delivery system of the present disclosure significantlyincreases the flux and efficiency of the patch. The presently disclosedmethylphenidate transdermal delivery system has increased drug loadingcapacity and drug release sustainability and achieved a desired skinpenetration rate and adhesion property.

In certain embodiment, the silicone adhesive layer comprises 10-50%,50-80%, 80-90%, 90-100% of silicone adhesive. In one embodiment, thesilicone adhesive layer comprises 100% silicone adhesive. In certainembodiment, the silicone adhesive layer has a thickness of about 1-5 μm,5-10 μm, 10-20 μm, 20-30 μm, 30-40 μm, 40-50 μm or 50-60 μm.

In one embodiment, the silicon adhesive layer is a uniform layer thathas even thickness throughout the layer. There is minimal intermixing ofthe silicone adhesive layer with the drug-containing matrix layer. Incertain embodiments, the silicone adhesive layer act as thebacking/impermeable layer. Hartwig R., Kanios D., Bonne S.; AcrylicPolymer Backing Films for Controlling In-Vitro Permeation and DeliveryProfile of Estradiol from Transdermal Drug Delivery Systems; AAPS 2004showed that adding acrylic polymer backing film could reduce thepermeation rate and delivery profile. The addition of a silicon adhesivelayer actually increases the permeation rate and delivery profile.

In certain embodiments, the silicone adhesive layer further comprisesadditional adhesives. Suitable adhesives include (pressure sensitiveadhesives made from silicone polymer and resin. The polymer to resinratio can be varied to achieve different levels of tack, which is usefulwhere the matrix layer is the skin contact layer of a device of thepresent disclosure. Specific examples of useful silicone adhesives forthis purpose which are commercially available include the standard DowCorning® BIO-PSA series (7-4400, 7-4500 and 7-4600 series) and the aminecompatible (endcapped) Dow Corning® BIO-PSA series (7-4100, 7-4200 and7-4300 series) manufactured by Dow Corning. In certain embodiments,adhesives include Dow Corning® BIO-PSA 7-4201, 7-4202, 7-4301, 7-4302,7-4501, 7-4502 and 7-4602, with BIO-PSA 7-4201, BIO-PSA 7-4301, BIO-PSA7-4302 or mixtures thereof, e.g., BIO-PSA 7-4201, BIO-PSA 7-4301 and/orBIO-PSA 7-4302.)

In certain embodiments, the silicone adhesive layer provides at least60-70% increase in flux as compared to a control transdermal system thatdoes not comprise the silicone adhesive layer. In certain embodiments,the silicone adhesive layer provides at least 60-70% increase in averagecumulative amount of drug delivery as compared to a control transdermalsystem that does not comprise the silicone adhesive layer.

Drug-Containing Matrix Layer

In certain embodiments, the drug-containing matrix layer comprisesrubber-based polymer. In certain embodiments, the rubber-based polymersinclude, but are not limited to, styrenic block polymers andcombinations thereof. Suitable styrenic block copolymer-based adhesivesinclude, but are not limited to, styrene-butadiene-styrene copolymer(SBS).

In certain embodiments, the drug-containing matrix layer comprises arubber-based polymer that comprises a hydrogenated synthetic hydrocarbontackifier. In certain embodiments, the hydrogenated synthetichydrocarbon tackifier is rosin esters, terpene and or hydrocarbon. Inone embodiment, the polymer matrix includes one or more C5 to C9hydrogenated hydrocarbon resins. In one embodiment, the polymer matrixdoes not include one or more C5 to C9 hydrogenated hydrocarbon resins.In one embodiment, the hydrogenated synthetic hydrocarbon is fullysaturated. In certain embodiments, the hydrogenated hydrocarbon ispartially saturated. In certain embodiments, the hydrogenatedhydrocarbon comprises at least 1, 2, 3, 4 carbon atoms that are notfully hydrogenated.

In certain embodiments, the drug-containing matrix layer comprises arubber-based polymer including natural or synthetic polyisoprene,polybutylene, polyisobutylene, styrene-butadiene polymers,styrene-isoprene-styrene block copolymers, hydrocarbon polymers, such asbutyl rubber, halogen-containing polymers, such as polyacrylic-nitrile,polytetrafluoroethylene, polyvinylchloride, polyvinylidene chloride, andpolychlorodiene, and other copolymers thereof. In some embodiments, thepolymer matrix comprises one or more polyisobutylene polymers. In someembodiments, the polymer matrix comprises one or morestyrene-isoprene-styrene block copolymers. In some embodiments, thepolymer matrix comprises one or more one or more polyisobutylenepolymers and one or more styrene-isoprene-styrene block copolymers.

In certain embodiments, the drug-containing matrix layer may exclude anyof the previously listed natural or synthetic polymers or copolymers asdisclosed above.

The drug-containing matrix layer may include a pressure sensitiveadhesive. The terms “pressure sensitive adhesive” means an adhesive thatforms an adhesive bond when pressure is applied to adhere the adhesivewith a surface. In certain embodiments, the degree of bond strength isproportional to the amount of pressure that is used to apply theadhesive to the surface.

In certain embodiments, the drug-containing matrix layer does notcontain acrylic polymers.

In certain embodiments, the drug-containing matrix layer comprises atackifier. In certain embodiments, the drug-containing matrix layer doesnot comprise a tackifier.

In certain embodiments, the drug-containing matrix layer comprises atackifier that is not present in the rubber-based polymer. In certainembodiment, the drug-containing matrix layer does not comprise atackifier except a hydrogenated synthetic hydrocarbon tackifier.

In certain embodiments, the tackifier present in the drug-containingmatrix layer is about 3-10%, about 10-30%, about 30-50%, about 50-60%,about 60-65%, about 65-70%, about 70-75%, about 75-80%, about 75-80%,about 80-90%, about 90-95%, about 95-96%, about 96-97%, about 97-98%,about 98-99%, by weight based on the total weight of the drug-containingmatrix layer. In certain embodiments, the tackifier is about 30-85% byweight based on the total weight of the drug-containing matrix layer. Incertain embodiments, the tackifier is about 30-60% by weight based onthe total weight of the drug-containing matrix layer.

In certain embodiments, the drug-containing matrix layer comprises anenhancer composition that enhances drug permeation. The enhancercomposition facilitates the absorption of the active agent through theskin of the subject.

In certain embodiments, the antioxidant may be present in an amountranging from about 0.001 to 5.0%, about 0.05%, about 0.001-0.005%, about0.005-0.01%, about 0.01-0.05%, about 0.05-0.1%, about 0.1-0.5%, about0.5-1%, about 1-3%, about 3-5% by weight based on the total weight ofthe drug-containing matrix layer.

In certain embodiments, the drug-containing matrix layer may containfillers which include, but are not limited to: metal oxides (such aszinc oxide and titanium oxide), metal salts (such as calcium carbonate,magnesium carbonate and zinc stearate), silicic acid compounds (such askaolin, talc, bentonite, Aerosil, hydrous silica, aluminum silicate,magnesium silicate and magnesium aluminometasilicate) and metalhydroxides (such as aluminum hydroxide). Where present, such fillers maybe 1 to 75%, such as 2 to 50% by weight based on the total weight of thedrug-containing matrix layer.

In certain embodiments, the drug-containing matrix layer includes asolvent which includes but is not limited to a volatile solvent or anon-volatile solvent (i.e., a solvent that is non-volatile as comparedto acetone, isopropanol or water, but may nonetheless exhibit somevolatility), such as dimethyl sulfoxide (DMSO), N-methylpyrrolidone,dimethyl isosorbide, propylene glycol, hexylene glycol and benzylalcohol. In one embodiment, the solvent is diethylene glycol monoethylether. In certain embodiments, the solvent is Transcutal® P. Thedrug-containing matrix layer comprises a solvent in an amount of about0.1-1%, about 1-5%, about 5-10%, about 10-15%, about 15-20%, about20-30% by weight based on the total weight of the drug-containing matrixlayer. In certain embodiments, the drug-containing matrix layercomprises one or more solubilizers and/or enhancers. In certainembodiments, the solubilizers and/or enhancers are ethyl acetate,isopropyl alcohol, methanol, tetrahydrofuran, oleic Acid, SPAN 80,isopropyl myristate, Brij 30, Tween 80, squalane, dipropylene glycol,limonens, N-lauroyl sarcosine, octanol, polyoxyethylene lauryl ether,Crodasinic LS 30, glycerine, Crodamol, glyceryl monooleate, oleylalcohol, glyceryl dibehenated, octyldodecanol, isopropyl palmitate,Di-tert-butyl-4-Methyl-Phenol, ethy loleate, dodecanol, myristylalcohol, oleyl oleate, N-Heptane, N-Hexane, isobutyl alcohol,polysorbate 80, chloroform.

The drug-containing matrix layer of the transdermal delivery system mayvary in thickness. In certain embodiments, the drug-containing matrixlayer has a thickness within a range that is sufficient to provide forthe desired extended delivery of a therapeutically effective amount ofthe active agent to the subject. In certain embodiments, the thicknessof the formulation is chosen in view of the desired transdermal deliveryrate of the active agent and the target dosage. In certain embodiments,the thickness of the drug-containing matrix layer is about 10 μm toabout 15 μm, about 15 μm to about 20 μm, about 20 μm to about 25 μm,about 25 μm to about 30 μm, about 30 μm to about 35 μm, about 35 μm toabout 40 μm, about 40 μm to about 45 μm, about 45 μm to about 50 μm,about 50 μm to about 55 μm or about 55 μm to about 150 μm.

Backing Layer

In certain embodiments, the transdermal delivery system includes abacking layer (e.g., support layer). The backing may be flexible to anextent that it can be brought into close contact with a desired topicallocation of a subject. The backing may be fabricated from a materialthat does not absorb the active agent, and does not allow the activeagent to be released from the backing side of the transdermalformulation. Backing materials of interest may be occlusive (i.e.,impermeable), semi-occlusive or breathable (permeable). The backing mayinclude, but is not limited to, non-woven fabrics, woven fabrics, films(including sheets), foils, porous bodies, foamed bodies, paper,composite materials obtained by laminating a film on a non-woven fabricor fabric, and combinations thereof. Non-woven fabric may include, butis not limited to, the following: polyolefin resins such as polyethyleneand polypropylene; polyester resins such as polyethylene terephthalate,polybutylene terephthalate and polyethylene naphthalate; rayon,polyamide, poly(ester ether), polyurethane, polyacrylic resins,polyvinyl alcohol, styrene-isoprene-styrene copolymers, andstyrene-ethylene-propylene-styrene copolymers; and combinations thereof.

Fabrics may include, but are not limited to: cotton, rayon, polyacrylicresins, polyester resins, polyvinyl alcohol, and combinations thereof.Films may include, but are not limited to the following: polyolefinresins such as polyethylene (including low density and high densitypolyethylene (LDPE, HDPE) and polypropylene; polyacrylic resins such aspolymethyl methacrylate and polyethyl methacrylate; polyester resinssuch as polyethylene terephthalate, poly-chloro-tri-fluoro-ethylene,acrylonitrile methyl acrylate copolymer, polybutylene terephthalate andpolyethylene naphthalate; and polyvinyl alcohol, ethylene-vinyl alcoholcopolymers, polyvinyl chloride, polystyrene, polyurethane,polyacrylonitrile, fluororesins, styrene-isoprene-styrene copolymers,styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetatecopolymers, polyamide, and polysulfone; and combinations thereof. Foilsmay include metallic foils, e.g., aluminum foils, etc. Papers mayinclude, but are not limited to, impregnated paper, coated paper, woodfree paper, Kraft paper, Japanese paper, glassine paper, syntheticpaper, and combinations thereof. Composite materials may include, butare not limited to, composite materials obtained by laminating theabove-described film on the above-described non-woven fabric or fabric.In certain embodiments, the backing includes a polyester, such aspolyethylene terephthalate (PET).

In certain embodiments, the backing layer is in contact with a surfaceof the drug-containing matrix layer. For example, where the transdermaldelivery system is configured so that one surface of the drug-containingmatrix layer contacts the skin upon application, the backing will be incontact with an opposing surface of the drug-containing matrix layer.

In certain embodiments, suitable backing layer includes ethylene vinylacetate films laminated to a polyester, ethylene vinyl acetate filmslaminated to a metallized polyester, polyethylene or polyolefinbackings. The backing layer should be thick enough to resist wrinklingwhich may arise upon prolonged periods in storage and through themovement of a subject's skin. Typically, the backing layer is from about50 microns to about 100 microns in thickness. In certain embodiments,the backing layer has a larger surface than the drug-containing matrixlayer. In certain embodiments, the backing layer ranges from about 0.01mm to at least 10 mm larger than the drug-containing matrix layer.

Release Liner

In certain embodiments, the transdermal delivery system comprises arelease liner. In certain embodiments, a release liner is provided onthe drug-containing matrix layer, and specifically on a surface of thedrug-containing matrix layer that is distal (i.e., opposite) from thebacking layer. The release liner may facilitate the protection of thedrug-containing matrix layer before use of the transdermal deliverysystem. In certain embodiments, the release liner is configured to beremovable from the drug-containing matrix layer without retaining thedrug-containing matrix layer.

The release liner may be any convenient material. In certainembodiments, the release liner includes polyesters, such as polyethyleneterephthalate, polypropylene and combinations thereof. In certainembodiments, the release liner includes a coated substrate, which, forexample, may be prepared by treating one side of polyethylene-coatedwood free paper, polyolefin-coated glassine paper, a polyethyleneterephthalate (polyester) film, a polypropylene film, with a siliconetreatment. In certain instances, the release layer includes a polyesterfilm with a silicone treatment.

Dosage and Delivery of Active Agents

According to the present disclosure, the inventors have found thatmethylphenidate may be administered to the human body via topicalapplication delivery for the purpose of treating Attention DeficitDisorder (ADD) and Attention Deficit/Hyperactivity Disorder (ADHD) ifthe transdermal delivery system comprises a silicone adhesive layer anddrug-containing matrix layer. In certain embodiments, themethylphenidate is delivered in an amount effective to achievesubstantially zero-order kinetics 2 hours after application of thetransdermal delivery system. The present composition would provide asteady release of methylphenidate to the patient via topical applicationroute. In certain embodiments, the transdermal delivery system has adelivery rate of about 0.5 mg/24 hours to about 100 mg/24 hours ofmethylphenidate. In certain embodiments, the transdermal delivery systemhas a delivery rate of about 2.5 mg/24 hours to about 60 mg/24 hours toachieve a therapeutically effective dose in a patient. Theadministration of methylphenidate orally is 20-60 mg per day. In certainembodiments, the topical application system contains about 20-180 mg ofmethylphenidate or an effective amount which will not crystallize in thesystem. In certain embodiments, the amount of methylphenidate in thetopical application system is effective to deliver at least 60 mg of thedrug to the patient. In certain embodiments, the size of the deliverypatch is about 2 cm² to about 60 cm². In certain embodiments, thetransdermal delivery system delivers about 5 mg per 24 hours andcontains about 26.4 mg of methylphenidate base per 10 cm².

In one embodiment, the transdermal delivery system disclosed hereincomprises methylphenidate or its pharmaceutically acceptable salt in anamount to provide a flux of at least 8 μg/cm² hr to achieve therapeuticblood levels of methylphenidate for at least 2-4, 4-8, 8-10, 10-12,12-14, 14-16, 16-18, 18-20, 20-22, or 22-24 hours.

In one embodiment, the transdermal delivery system disclosed hereincomprises methylphenidate or its pharmaceutically acceptable salt in anamount to provide a dose of at least 5 mg to a patient over 8 hours witha flux of at least 8 μg/cm² hr for at least 2 hours.

In one embodiment, the transdermal delivery system disclosed hereincomprises methylphenidate or its pharmaceutically acceptable salt in anamount sufficient to achieve blood levels of methylphenidate in therange of 1 ng/ml to 25 ng/ml for at least 16 hours.

In one embodiment, the transdermal delivery system disclosed hereincomprising methylphenidate or its pharmaceutically acceptable salt in arubber-based adhesive carrier comprising a hydrogenated synthetichydrocarbon tackifier, wherein the methylphenidate is present in anamount sufficient to achieve substantially zero order kinetics fordelivery to the skin or mucosa of a patient in need thereof over aperiod of time at least 2 hours, wherein the methylphenidate is presentat a therapeutically effective amount that is substantially free ofcrystals.

The amount of a composition that will be effective in the treatment orprophylactic treatment of Attention Deficit Disorder (ADD) and/orAttention Deficit/Hyperactivity Disorder (ADHD) can be determined bystandard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on the seriousness of thedisease or disorder, and should be decided according to the judgment ofthe practitioner and each patient's circumstances.

Suitable doses of the drug for transdermal delivery are in the range of0.5 mg/24 hours to 100 mg/24 hours depending on the area to which thecompound is administered. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.Such animal models and systems are well known in the art.

In certain embodiment, the transdermal delivery system is applied to asubject shortly before the subject goes to sleep. In one embodiment, thetransdermal delivery system is applied to a subject 8-10 hours prior towaking up in the morning. In one embodiment, the transdermal deliverysystem is applied to a subject shortly after awaken from sleep in themorning. In one embodiment, the transdermal delivery system is removedprior to going to sleep in the evening. In certain embodiments, thetransdermal delivery system is applied within 2 hours prior to engagingat work or school or other activities while awake. In certainembodiments, the transdermal delivery system is applied to a subject for2-4, 4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-22, 22-24hours.

As used herein, the term, “flux” is defined as the absorption of thedrug through the skin or mucosa, and is described by Fick's first law ofdiffusion:J=−D(dCm/dx),where J is the flux in g/cm2/sec, D is the diffusion coefficient of thedrug through the skin or mucosa in cm²/sec and Dcm/dx is theconcentration gradient of the drug across the skin or mucosa.

The inventors have found that there is a relatively wide range ofpermeability of normal human skin to methylphenidate and thispermeability not only varies from individual to individual and site tosite, but is also dependent upon the chemical form of the drug. Incertain embodiments, the methylphenidate in the transdermal deliverysystem is in the base form or a base/basic salt combination, or anester.

In certain embodiments, a therapeutically effective dose ofmethylphenidate achieves a therapeutic effect, and is typically in therange of about 0.05 mg/kg to about 1.0 mg/kg/day for both children andadults, and more preferably of about 0.075 mg/kg/day to about 0.3mg/kg/day.

The presently disclosed transdermal delivery system attainssubstantially zero-order delivery 6 hours after application to asubject. The transdermal delivery system sustains a substantiallyzero-order delivery of methylphenidate or its pharmaceutical saltsthereof for at least 18 hours, 20 hours or 24 hours. This is ensured byproviding enough methylphenidate in the topical composition so as todeliver 15 to 40% of the drug in the first 18 hours.

In one embodiment, the disclosed transdermal delivery system attains atleast 18 hours of substantially zero-order delivery. The siliconeadhesive layer allows sufficient amounts of methylphenidate to be loadedinto the composition, while preserving the methylphenidate in the activeform needed for at least 18 hours of substantially zero-order delivery.

The presently disclosed system and methods of delivery ofmethylphenidate in therapeutic amounts for continuous periods in topicalapplication systems which rely primarily on skin or mucosa permeabilityto control drug input rate. It is also contemplated that delivery of thedrug can be from a rate controlled system in which the system itselfcontrols the maximum rate at which the drug is delivered through theskin or mucosa.

The phrase, “substantially zero-order” as used herein means delivery ofmethylphenidate through the skin or mucosa at a rate which isapproximately constant once steady state is attained. Typicalvariability contemplated within the scope of this meaning is about a 30%to about 40% difference from the mean in the blood levels ofmethylphenidate at steady state (3-10 hours after administration).

While the actual flux may vary, in certain embodiments, (e.g., asdetermined using the skin permeation assay in the Section 6 Examplesbelow) skin permeation rates are about 3-4 μg/cm²/hr, about 4-5μg/cm²/hr, about 5-6 μg/cm²/hr, about 6-7 μg/cm²/hr, about 7-8μg/cm²/hr, about 8-9 μg/cm²/hr, about 9-10 μg/cm²/hr, about 10-11μg/cm²/hr, or about 11-12 μg/cm²/hr, about 12-15 μg/cm²/hr, about 15-20μg/cm²/hr, about 20-25 μg/cm²/hr, about 25-30 μg/cm²/hr, about 30-35μg/cm²/hr, about 35-40 μg/cm²/hr, about 40-45 μg/cm²/hr, or about 45-50μg/cm²/hr.

In certain embodiments, the flux is about 13-44 μg/cm² hr.

In certain embodiments, the transdermal delivery systems are formulatedto provide a cumulative delivered amount (also referred to herein ascumulative flux) of the active agent to a subject when the formulationis applied to the skin of a subject for an extended period of time asdescribed infra. In certain embodiments, the transdermal formulationsare configured to provide a cumulative delivered amount of the activeagent of about 1-100 μg/cm², about 100-150 μg/cm², about 150-200 μg/cm²,about 200-250 μg/cm², about 250-300 μg/cm², about 300-350 μg/cm², about350-400 μg/cm², about 400-450 μg/cm², about 450-500 μg/cm², about500-550 μg/cm², about 550-600 μg/cm², about 600-650 μg/cm², 650-700μg/cm², about 700-750 μg/cm², 750 m-800 μg/cm², 800-850 μg/cm2, about850-900 μg/cm², about 900-950 μg/cm², or about 950-1000 μg/cm².

The size (i.e., area) of the transdermal delivery system may vary, butis within a range of the active agent to the subject. It is alsoimportant that the subject wearing the transdermal delivery system findsthe system to be easy to apply and comfortable to use for a period oftime so as to improve compliance. In certain embodiments, the size ofthe formulation is chosen in view of the desired transdermal flux rateof the active agent and the target dosage. In certain embodiments, thetransdermal delivery system has a size that is about 2-6 cm², about 6-10cm², about 10-20 cm², about 20-30 cm², about 30-40 cm², about 40-50 cm²,about 50-100 cm², about 100-130 cm², about 130-140 cm², about 140-150cm² or about 150-200 cm².

The transdermal delivery system of the present disclosure is formulatedto provide a therapeutically effective amount of the active agent to asubject when the topical patch is applied to a skin site of a subjectfor an extended period of time (e.g., a multi-day period of time). Forexample, the extended period of time may be a period of time that isabout 6-12 hours, about 12-24 hours, about 1-2 days.

In certain embodiments, various formulations, human pharmacokineticsprofile and skin permeation properties are shown in Tables 1, 2 and 3.In certain embodiments, the AUC_(0-t), is about 80-120 h·ng/mL, 120-160h·ng/mL, 160-200 h·ng/mL, 200-240 h·ng/mL, 240-280 h·ng/mL, 280-320h·ng/mL, 320-360 h·ng/mL, 360-400 h·ng/mL 400-440 h·ng/mL 440-480h·ng/mL. In certain embodiments, the AUC_(0-∞) is about 80-120 h·ng/mL,120-160 h·ng/mL, 160-200 h·ng/mL, 200-240 h·ng/mL, 240-280 h·ng/mL,280-320 h·ng/mL, 320-360 h·ng/mL, 360-400 h·ng/mL 400-440 h·ng/mL440-480 h·ng/mL. In certain embodiments, the C_(max) is about 8-12ng/mL, 12-16 ng/mL, 16-20 ng/mL, 20-24 ng/mL, 24-28 ng/mL, 28-32 ng/mL,32-36 ng/mL, 36-40 ng/mL, 40-44 ng/mL. In certain embodiments, theT_(max), is 4-6 hrs, 6-8 hrs, 8-10 hrs, 10-12 hrs, 12-14 hrs.

An aspect of the transdermal delivery system of the present disclosureis that it may be stored for extended periods of time withoutsignificant degradation and/or significant reduction in activity of theactive agent. In certain embodiments, the drug-containing matrix layercomprising methylphenidate or its pharmaceutically acceptable salt isstable for at least 1 year, 2 years, 3 years, 4 years, 5 years, or 6years. In certain embodiments, the transdermal delivery system ismaintained at 25° C.±2° C./60% RH±5% RH.

Methods of Use

In one embodiment, disclosed herein is a method of treating attentiondeficit disorder and attention deficit/hyperactivity disorder comprisingtopically administering methylphenidate transdermal delivery systemwherein the methylphenidate is present in an amount sufficient toachieve substantially zero order kinetics for delivery to the skin ormucosa of a patient in need thereof over a period of time at least about2-4, 4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, 20-22, 22-24hours, wherein the transdermal delivery system comprises a siliconelayer and a drug-containing matrix layer.

In one embodiment, the methylphenidate is present in an amountsufficient to permit a delivery rate from about 5-10 mg, 10-15 mg, 15-20mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-75 mg, 75-80 mg/24 hours in orderto achieve a therapeutically effective dose in a patient.

In one embodiment, the transdermal delivery system is formulated fordaily application.

In one embodiment, disclosed herein is a method of treating attentiondeficit disorder (ADD) or attention deficit/hyperactivity disorder(ADHD), comprising transdermal administration of methylphenidate or itspharmaceutically acceptable salt to an individual with ADD or ADHD, at arate in excess of 8 μg/cm²/hr.

A method of treating attention deficit disorder (ADD) or attentiondeficit/hyperactivity disorder (ADHD), comprising transdermaladministration of methylphenidate or its pharmaceutically acceptablesalt to an individual with ADD or ADHD, at a rate in excess of 0.15mg/kg/day.

Methods of Making the Transdermal Delivery System

Aspects of the present disclosure also include methods of producing thetransdermal delivery system as disclosed above. In certain embodiment, asilicon adhesive layer is applied to a backing. In certain embodiments,the method includes forming a mixture by mixing methylphenidate or itspharmaceutically acceptable salt with one or more solvents, arubber-based polymer to form a drug-containing matrix layer. In certainembodiments, the polymer is styrene-butadiene block copolymer comprisinga hydrogenated synthetic hydrocarbon tackifier.

The silicone adhesive layer is first applied to the backing layer. Thedrug-containing matrix mixture is then applied to the silicone adhesivelayer that is on top of the backing. The method may further includeapplying a release liner to the drug-containing matrix layer on the sidethat is opposite to the backing. In certain instances, the method ofmaking the transdermal delivery system further includes placing thetransdermal formulation into a package forming a kit. After placing thetransdermal formulation into the package, the method may include sealingthe package.

EXAMPLES

The following examples illustrate the synthesis and use ofrepresentative embodiments provided herein. These examples are notintended, nor are they to be construed, as limiting the scope of theclaimed subject matter. It will be clear that the scope of subjectmatter may be practiced otherwise than as particularly described herein.Numerous modifications and variations of the subject matter are possiblein view of the teachings herein and, therefore, are within the scope theclaimed subject matter.

Materials and Methods

The transdermal system are manufactured according to known methodologysuch as blending (mixing) the polymer(s), drug, and other excipientswith appropriate amount in the presence of an appropriate solvent, suchas a volatile organic solvent, casting the wet blend onto a releaseliner, followed by evaporation of the volatile solvent(s) at appropriatedrying conditions, laminating the adhesive layer, drug-containing matrixlayer and the release liner onto a backing film.

The flux can be measured with a standard procedure using Franz diffusioncells, and the experiments were done on human cadaver skin. With Franzcells, in each Franz diffusion cell a disc (diameter of 25 mm) of humancadaver skin is placed on the receptor compartment. A transdermaldelivery system is cut the same size as the skin and placed over thediffusion area in the center of the receptor. The donor compartment isthen added and clamped to the assembly. At time 0, receptor mediumsolution 14 mL is added into the receptor compartment and the cellmaintained at 32° C. Samples of the receptor compartment are takenperiodically to determine the skin flux and analyzed by HPLC.

Flux Test

Flux tests were conducted using one embodiment of the transdermaldelivery system. The following method was used in preparation andtesting of the transdermal delivery system. First remove protectivereleasing liner of the patch and revealing the adhesive side of patch.Then attach the patch on to a human cadaver skin with adhesive sidetoward skin with gentle pressure against the back of the patch, toensure firm adhesion. Next, secure the patch/skin complex between upperand lower chamber of Franz diffusion cell with skin side toward lowerchamber, wherein the lower chamber is filled with buffer and heated inorder to simulate conditions of the human body. By measuringmethylphenidate concentration of the buffer in the lower chamber of theFranz diffusion cell, the permeated amount and flux of methylphenidateof the tested patch may be determined.

Flux data were obtained from two embodiments of the methylphenidatetransdermal delivery system. In one embodiment, the transdermal deliverysystem comprises about 8% methylphenidate free base with no excipientwhereas the second embodiment comprises about 8% methylphenidate withabout 25% squalane. The transdermal delivery system achieved a flux ofabout 0.0248 mg/cm²/hour whereas another embodiment, the transdermaldelivery system achieved a flux of about 0.0530 mg/cm²/hour. Theseresults illustrate the efficacy of squalane in increasing flux of themethylphenidate transdermal delivery system. The results are presentedin Table 1 below:

TABLE 1 Formu- Flux (mg/ lation Methylphenidate Squalane Cyclomethiconecm²/hour) Ex 1 8% 0% 0% 0.0248 Ex 2 8% 25% 0% 0.0530

As Table 1 illustrates, increase in the weight % of squalane resulted inincrease in the flux rate. Notably, the transdermal delivery systemcomprising 25% weight percentage of squalene resulted in about 40% toabout 50% increase in flux as compared to formulation 1 that does notcomprise any excipient. Embodiments with cyclomethicone also resulted inhigher flux than the embodiment without any excipient. An additionaltest was conducted to show that the methylphenidate transdermal deliverysystem is able to sustain delivery of methylphenidate at about zeroorder kinetics for over 8 hours of application.

In Vivo Pharmacokinetics Studies

The pharmacokinetics studies of a transdermal patch containingmethylphenidate is assessed in 12 healthy volunteers. The transdermalsystem is apply to the healthy subjects topically on their hip for 9hours. The blood samples were collected periodically. Methylphenidateconcentrations were measured in blood plasma using a validatedchromatographic method developed. This method was validated todemonstrate adequate sensitivity, specificity, linearity, recovery,accuracy and precision. The pharmacokinietcs parameters such asAUC_(0-t), AUC_(0-∞), C_(max), T_(max), t_(1/2), were calculated usingWinNonlin Pro 5.3 and above. The results are shown in Table 2.

TABLE 2 Pharmacokinietcs Results Pharmacokinetic Parameters Ex 8 AUC0-t(h · ng/mL) 129.2 ± 39.15 AUC0-∞ (h · ng/mL) 137.12 ± 39.99  Cmax(ng/mL) 15.37 ± 5.37  Tmax (h) 9.75 ± 0.62 t½ (h) 4.21 ± 0.67

Table 3 shows the relationship between % weight of methylphenidate andits effect on peel adhesion. Results are also shown in FIG. 4.

TABLE 3 Example 3 Example 4 Example 5 Example 6 Ingredient % w/w % w/w %w/w % w/w Methylphenidate 0 8 12.5 17 Limonene 0 15 15 15 Duro Tak87-6911 100 77 72.5 68 Peel adhesion (Winch) 2449.85 ± 26.24 1886.54 ±98.49 2179.66 ± 102.24 2284.95 ± 115.75

Example 7 Drug Composition Using Bilayer Adhesive Matrix Ingredient %w/w Methylphenidate 17 Duro Tak 87-6911 83 (Blacking Layer without Drug)Silicone BIO PSA 7-4102 100 Flux (μg/cm²/hr) 13.12 Example 8 DrugComposition Using Bilayer Adhesive Matrix Ingredient % w/wMethylphenidate 17 Duro Tak 87-6911 83 (Blacking Layer without Drug)Silicone BIO PSA 7-4302 100 Flux (μg/cm²/hr) 20.67 Example 9 DrugComposition Using Bilayer Adhesive Matrix Ingredient % w/wMethylphenidate 17 Duro Tak 87-6911 83 (Blacking Layer without Drug)Silicone BIO PSA 7-4602 100 Flux (μg/cm²/hr) 14.90 Example 10 DrugComposition Using Bilayer Adhesive Matrix Ingredient % w/wMethylphenidate 17 Duro Tak 87-6911 83 Flux (μg/cm²/hr) 9.78

In Vitro Dissolution Studies

Patch formulation composition as described in Example 10 were dissolvedin dissolution buffer 0.01N HCl. Samples were collected at 0.5, 1.5, 3,4, 9 and 12 hours. Methylphenidate content was determined by HPLC andthe results are shown in FIG. 6.

It can be concluded that in less than 12 hours, there are more than 80%of the methylphenidate from Example 8 that will be released.

In one embodiment, the transdermal delivery system releases at leastabout 80% methylphenidate within 12 hours in an in vitro dissolutionmedia at about pH1.2.

Stability Studies (Crystal Growth Observation and Impurity Analysis forBatch Compositions Using Silicone Adhesive and SBS Adhesive

Products made from Example 8 and Example 10 were inspected forappearance, including color and crystal growth. They were thenseparately storage for 2 weeks at stress condition for as long as onemonth at accelerated aging conditions (40° C./75% RH.) and control roomtemperature conditions (25° C./60% RH.) and inspected. The results areset out below:

Total Impurities (%) 60° C.75% RH Crystal Growth Observation Sample Name1 weeks 25° C.60% RH 40° C.75% RH 60° C.75% RH Ex 8 1.50 No color changeNo color change No color change Crystal Not Crystal Not Crystal NotObserved Observed Observed 1 Mo 1 Mo 1 Weeks Ex 9 2.17 No color changeNo color change No color change Crystal Not Crystal Not Crystal NotObserved Observed Observed 1 Mo 1 Mo 1 weeksImpurity is less than 5% and showed no crystal growth under all theconditions.

Formulations

Various adhesives were tested to determine the maximum amount ofmethylphenidate could be dissolved. The results are provided below:

Drug Composition in Duro Tak 87-6911 as Adhesive Matrix % w/w IngredientExample 11 Example 12 Methylphenidate 20 40 Duro Tak 87-6911 q.s q.sObservation soluble Soluble

Drug Composition in Acritical Adhesive Matrix % w/w Ingredient Example13 Example 14 Example 15 Methylphenidate 5 5 5 Duro Tak 387-4287 q.sDuro Tak 387-2852 q.s Duro Tak 387-2510 q.s Observation soluble solubleSoluble

Drug Composition in Silicone Adhesive Matrix % w/w Ingredient Ex 16 Ex17 Methylphenidate 5 5 Dow Corning 7-6302 q.s Dow Corning 7-9900 q.sObservation Off white incompatible

Skin Permeation

Skin permeation of various formulations were tested. The results areprovided in FIGS. 2 and 3. Higher amount of the methylphenidate in theadhesives will increase the penetration. However, while methylphenidateis highly soluble in the Duro Tak 87-6911, when the amount ofmethylphenidate is over 40%, it was not able to coat as a film. Asindicated that in FIG. 8 there is a linear relationship between the drugloading and permeation rate when the methylphenidate is less than 20%weight.

Examples 18-20 illustrate that the higher the drug loading, the higherthe permeation rate.

Example 18 Drug Composition Using Bilayer Adhesive Matrix Ingredient %w/w Methylphenidate 8 Duro Tak 87-6911 92 (Blacking Layer without Drug)Silicone BIO PSA 7-4302 100 Example 19 Drug Composition Using BilayerAdhesive Matrix Ingredient % w/w Methylphenidate 11 Duro Tak 87-6911 89(Blacking Layer without Drug) Silicone BIO PSA 7-4302 100 Example 20Drug Composition Using Bilayer Adhesive Matrix Ingredient % w/wMethylphenidate 20 Duro Tak 87-6911 80 (Blacking Layer without Drug)Silicone BIO PSA 7-4302 100Exemplary Systems and Methods are Set Out in the Following Items

Item 1. A transdermal delivery system comprising:

-   (i) a silicone adhesive layer; and-   (ii) a drug-containing matrix layer comprising: (a) methylphenidate    or its pharmaceutically acceptable salt; and (b) a rubber-based    polymer that comprises a hydrogenated synthetic hydrocarbon    tackifier.

Item 2. The transdermal delivery system of the preceding item, whereinthe rubber-based polymer is styrene-butadiene block copolymer rubber.

Item 3. The transdermal delivery system of anyone of the preceding itemsconsisting essentially of a backing layer, the silicon adhesive layer,the drug-containing matrix layer, and a release liner.

Item 4. The transdermal delivery system of anyone of the precedingitems, wherein the methylphenidate or its pharmaceutically acceptablesalt is about 10 to about 20% by weight based on the total weight of thedrug-containing matrix layer.

Item 5. The transdermal delivery system of anyone of the precedingitems, wherein the methylphenidate or its pharmaceutically acceptablesalt is about 12, about 15 or about 17% by weight based on the totalweight of the drug-containing matrix layer.

Item 6. The transdermal delivery system of anyone of the precedingitems, wherein the hydrogenated synthetic hydrocarbon tackifier is about10-80% by weight based on the total weight of the drug-containing matrixlayer.

Item 7. The transdermal delivery system of anyone of the preceding itemswherein the silicone adhesive layer comprises 100% of silicone adhesive.

Item 8. The transdermal delivery system of anyone of the precedingitems, wherein the drug-containing matrix layer further comprises anexcipient.

Item 9. The transdermal delivery system of anyone of the precedingitems, wherein the drug-containing matrix layer has a thickness fromabout 20 μm to about 48 μm.

Item 10. The transdermal delivery system of anyone of the precedingitems, wherein the size of a unit of the system has a dimension of about2-60 cm².

Item 11. The transdermal delivery system of anyone of the precedingitems, wherein the system has a flux of about 18-25 μg/cm²/hr.

Item 12. The transdermal delivery system of anyone of the precedingitems, wherein the system delivers methylphenidate and itspharmaceutically acceptable salts over a period of time of at leastabout 8-24 hours.

Item 13. The transdermal delivery system of anyone of the precedingitems, wherein the methylphenidate or its pharmaceutically acceptablesalt is about 15-19% by weight, wherein the styrene-butadiene blockcopolymer rubber comprises a hydrogenated synthetic hydrocarbontackifier which is about 81-85% by weight based on the total weight ofthe drug-containing matrix layer.

Item 14. The transdermal delivery system of anyone of the precedingitems, wherein the styrene-butadiene-styrene block copolymer comprises ahydrogenated synthetic hydrocarbon tackifier which is about 30-60% byweight based on the total weight of the drug-containing matrix layer.

Item 15. The transdermal delivery system of anyone of the precedingitems, wherein the silicone layer increases flux by about 50-80% ascompared to a control transdermal delivery system without the siliconelayer.

Item 16. The transdermal delivery system of anyone of the precedingitems, wherein the excipient does not degrade the methylphenidate or itspharmaceutically acceptable salt.

Item 17. The transdermal delivery system of anyone of the precedingitems, wherein the drug-containing matrix layer further comprises apermeation enhancer.

Item 18. The transdermal delivery system of anyone of the precedingitems, wherein the permeation enhancer comprises about 5% to about 25%of the total weight of the drug-containing matrix layer.

Item 19. The transdermal delivery system of anyone of the precedingitems wherein the transdermal delivery system delivers themethylphenidate or its salts with substantially zero-order kinetics.

Item 20. The transdermal delivery system of anyone of the precedingitems wherein the methylphenidate or its pharmaceutically acceptablesalt comprises less than 5% of impurities.

Item 21. The transdermal delivery system of anyone of the precedingitems wherein the transdermal delivery system has a shelf-life of atleast 2 years at room temperature.

Item 22. The transdermal delivery system of anyone of the precedingitems wherein the drug-containing matrix layer is color-stable and lackscrystal growth of methylphenidate or its pharmaceutically acceptablesalt over an extended storage period of at least 2 years.

Item 23. The transdermal delivery system of anyone of the precedingitems wherein the transdermal delivery system releases at least about20-60% methylphenidate within 12 hours after administration to asubject.

Item 24. The transdermal delivery system of anyone of the precedingitems wherein the transdermal delivery system releases at least about30% methylphenidate within 12 hours after administration to a subject.

Item 25. The transdermal delivery system of anyone of the precedingitems wherein the transdermal delivery system releases at least about80% methylphenidate within 12 hours in the in vitro dissolution media atabout pH 1.2.

Item 26. The transdermal delivery system of anyone of the precedingitems wherein the transdermal delivery system has a flux rate rangingfrom about 6 μg/cm²/hr-100 μg/cm²/hr between 2-18 hours after treatmentis initiated.

Item 27. A method of treating attention deficit disorder, attentiondeficit/hyperactivity disorder, postural orthostatic tachycardiasyndrome or narcolepsy comprising topically administeringmethylphenidate and its pharmaceutically acceptable salts in atransdermal delivery system wherein the methylphenidate is present in anamount sufficient to achieve substantially zero order kinetics fordelivery to the skin or mucosa of a patient in need thereof over aperiod of time at least 18 hours, wherein the transdermal deliverysystem comprises a silicone adhesive layer, a drug-containing matrixlayer comprising a rubber-based polymer that comprises a hydrogenatedsynthetic hydrocarbon tackifier.

Item 28. A method of making the transdermal delivery system of precedingitems 1 to 26 comprising the steps of:

-   (a) dissolving a desired amount of methylphenidate with a    rubber-based polymer comprising a hydrogenated synthetic hydrocarbon    tackifier to form a mixture;-   (b) deaerating the mixture;-   (c) laminating a silicon layer onto a supportive backing layer;-   (d) laminating the mixture onto the silicon layer to form a wet    film;-   (e) drying the wet film to form a dry film;-   (f) laminating the dry film with a releasing liner; and-   (g) optionally cropping the dry film into a desired dimension.

The disclosure is not to be limited in scope by the specific embodimentsdescribed herein. Indeed, various modifications of the invention inaddition to those described will become apparent to those skilled in theart from the foregoing description and accompanying figures. Suchmodifications are intended to fall within the scope of the appendedclaims. In fact, all the individual embodiments can be combined with oneor more individual embodiments that are disclosed herein.

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

What is claimed is:
 1. A transdermal delivery system comprising: (i) asilicone adhesive layer; and (ii) a drug-containing matrix layercomprising: (a) methylphenidate or its pharmaceutically acceptable salt;and (b) a rubber-based polymer that comprises a hydrogenated synthetichydrocarbon tackifier, wherein the transdermal delivery system has aflux rate ranging from about 6 μg /cm²/hr -100 μg /cm²/hr between 2-18hours after treatment is initiated, and wherein the silicone adhesivelayer comprises 10-100% of silicone adhesive.
 2. The transdermaldelivery system of claim 1, wherein the rubber-based polymer isstyrene-butadiene block copolymer rubber.
 3. The transdermal deliverysystem of claim 2, wherein the methylphenidate or its pharmaceuticallyacceptable salt is about 10-20% by weight, wherein the styrene-butadieneblock copolymer rubber comprises a hydrogenated synthetic hydrocarbontackifier which is about 10-85% by weight based on the total weight ofthe drug-containing matrix layer.
 4. The transdermal delivery system ofclaim 3 wherein the transdermal delivery system releases at least about10% methylphenidate within 12 hours after administration to a subject.5. The transdermal delivery system of claim 3, wherein the transdermaldelivery system releases about 40%-80% methylphenidate within 12 hoursafter administration to a subject.
 6. The transdermal delivery system ofclaim 3, wherein the transdermal delivery system releases at least about5% methylphenidate within 12 hours after administration to a subject. 7.The transdermal delivery system of claim 2, wherein thestyrene-butadiene block copolymer comprises a hydrogenated synthetichydrocarbon tackifier which is about 60-85% by weight based on the totalweight of the drug-containing matrix layer.
 8. The transdermal deliverysystem of claim 2, wherein the methylphenidate or its pharmaceuticallyacceptable salt is about 10-30% by weight based on the total weight ofthe drug-containing matrix layer, wherein the styrene-butadiene blockcopolymer rubber comprises a hydrogenated synthetic hydrocarbontackifier which is about 3-90% by weight based on the total weight ofthe drug-containing matrix layer.
 9. The transdermal delivery system ofclaim 1 consisting essentially of a backing layer, the silicone adhesivelayer, the drug-containing matrix layer, and a release liner.
 10. Thetransdermal delivery system of claim 1, wherein the methylphenidate orits pharmaceutically acceptable salt is about 10% to about 20% by weightbased on the total weight of the drug-containing matrix layer.
 11. Thetransdermal delivery system of claim 1, wherein the methylphenidate orits pharmaceutically acceptable salt is about 12%, about 15% or about17% by weight based on the total weight of the drug-containing matrixlayer.
 12. The transdermal delivery system of claim 1, wherein thehydrogenated synthetic hydrocarbon tackifier is about 10-80% by weightbased on the total weight of the drug-containing matrix layer.
 13. Thetransdermal delivery system of claim 1 wherein the silicone adhesivelayer comprises 90-100% of silicone adhesive.
 14. The transdermaldelivery system of claim 1, wherein the drug-containing matrix layerfurther comprises an excipient.
 15. The transdermal delivery system ofclaim 14 wherein the excipient does not degrade the methylphenidate orits pharmaceutically acceptable salt.
 16. The transdermal deliverysystem of claim 1, wherein the drug-containing matrix layer has athickness from about 10 μm to about 100 μm.
 17. The transdermal deliverysystem of claim 1, wherein the size of a unit of the system has adimension of about 2-60 cm².
 18. The transdermal delivery system ofclaim 1, wherein the system has a flux of about 10-30 μg/cm²/hr.
 19. Thetransdermal delivery system of claim 1, wherein the system deliversmethylphenidate and its pharmaceutically acceptable salts over a periodof time of at least about 3-24 hours.
 20. The transdermal deliverysystem of claim 1, wherein the silicone layer increases flux by about50-80% as compared to a control transdermal delivery system without thesilicone layer.
 21. The transdermal delivery system of claim 1, whereinthe drug-containing matrix layer further comprises a permeationenhancer.
 22. The transdermal delivery system of claim 21, wherein thepermeation enhancer comprises about 5% to about 25% of the total weightof the drug-containing matrix layer.
 23. The transdermal delivery systemof claim 1 wherein the transdermal delivery system delivers themethylphenidate or its salts with substantially zero-order kinetics. 24.The transdermal delivery system of claim 1 wherein the methylphenidateor its pharmaceutically acceptable salt comprises less than 5% ofimpurities.
 25. The transdermal delivery system of claim 1 wherein thetransdermal delivery system releases at least about 10% methylphenidatewithin 12 hours after administration to a subject.
 26. The transdermaldelivery system of claim 1 wherein the transdermal delivery systemreleases at least about 80% methylphenidate within 12 hours in an invitro dissolution media at about pH 1.2.
 27. The transdermal deliverysystem of claim 1, wherein the methylphenidate or its pharmaceuticallyacceptable salt is about 30% by weight based on the total weight of thedrug-containing matrix layer.
 28. The transdermal delivery system ofclaim 1, wherein the methylphenidate or its pharmaceutically acceptablesalt is about 20% or about 30% by weight based on the total weight ofthe drug-containing matrix layer.
 29. The transdermal delivery system ofclaim 1, wherein the hydrogenated synthetic hydrocarbon tackifier isabout 3-90% by weight based on the total weight of the drug-containingmatrix layer.
 30. The transdermal delivery system of claim 1, whereinthe hydrogenated synthetic hydrocarbon tackifier is about 70-95% byweight based on the total weight of the drug-containing matrix layer.31. The transdermal delivery system of claim 1, wherein the siliconeadhesive layer comprises a drug.
 32. The transdermal delivery system ofclaim 1, wherein the silicone adhesive layer comprises 100% of siliconeadhesive.
 33. The transdermal delivery system of claim 1, wherein thedrug-containing matrix layer has a thickness from about 10 μm to about150 μm.
 34. The transdermal delivery system of claim 1, wherein the sizeof a unit of the system has a dimension of about 2-100 cm².
 35. Thetransdermal delivery system of claim 1, wherein the system has a flux ofabout 10-60 μg/cm2/hr.
 36. The transdermal delivery system of claim 1,wherein the transdermal delivery system releases about 40%-80%methylphenidate within 12 hours after administration to a subject. 37.The transdermal delivery system of claim 1, wherein the transdermaldelivery system releases at least about 5% methylphenidate within 12hours after administration to a subject.
 38. The transdermal deliverysystem of claim 1 wherein the transdermal delivery system releases atleast about 40% methylphenidate within 12 hours in an in vitrodissolution media at about pH 1.2.
 39. A transdermal delivery systemcomprising: (i) a silicone adhesive layer; and (ii) a drug-containingmatrix layer comprising: (a) methylphenidate or its pharmaceuticallyacceptable salt; and (b) a rubber-based polymer that comprises ahydrogenated synthetic hydrocarbon tackifier, wherein the transdermaldelivery system has a flux rate ranging from about 6 μg/cm²/hr -100μg/cm²/hr between 2-18 hours after treatment is initiated, and whereinthe silicone adhesive layer comprises 10-100% of silicone adhesive,wherein the drug-containing matrix layer is color-stable and lackscrystal growth of methylphenidate or its pharmaceutically acceptablesalt over an extended storage period of at least 6 months at roomtemperature.
 40. A transdermal delivery system comprising: (i) asilicone adhesive layer; and (ii) a drug-containing matrix layercomprising: (a) methylphenidate or its pharmaceutically acceptable salt;and (b) a rubber-based polymer that comprises a hydrogenated synthetichydrocarbon tackifier, wherein the transdermal delivery system has aflux rate ranging from about 6 μg/cm²/hr -100 μg/cm²/hr between 2-18hours after treatment is initiated, and wherein the methylphenidate orits pharmaceutically acceptable salt is about 4-60 mg.
 41. A transdermaldelivery system comprising: (i) a silicone adhesive layer; and (ii) adrug-containing matrix layer comprising: (a) methylphenidate or itspharmaceutically acceptable salt; and (b) a rubber-based polymer thatcomprises a hydrogenated synthetic hydrocarbon tackifier, wherein thetransdermal delivery system has a flux rate ranging from about 6μg/cm²/hr -100 μg/cm²/hr between 2-18 hours after treatment isinitiated, and wherein the methylphenidate or its pharmaceuticallyacceptable salt is about 20-180 mg.